Parkinson's Disease (PD) is a progressive neurodegenerative disease which is characterized by degeneration of the nigrostriatal dopaminergic pathway resulting in production of bradykinesia in combination with rigidity and tremor. Although the etiology of PD is not clearly understood, factors such as oxidative stress are now strongly implicated in the selective loss of dopaminergic neurons. Currently, no ideal therapies are available for slowing the progression of the degeneration process and at the same time relieving symptomatic abnormalities associated with this disease. Interest in dopamine agonists in PD therapy is growing recently. Dopamine agonists, besides providing symptomatic relief in PD with less motor complications, have also been shown to act as neuroprotective agents. In this regard, the relatively recently discovered dopamine receptor subtype D3 has become an interesting target for drug development for PD for several reasons. DS-preferring agonists e.g. pramipexole, has been shown to provide additional beneficial neuroprotective effects over that seen with D2-selective agonists. In this proposal, we plan to develop novel DS-selective compounds to explore and understand the role of this receptor subtype in producing antiparkinsonian effect in an animal model of PD. In our preliminary study, we have developed a novel molecular template exhibiting preferential affinity for the D3- compared to the D2-receptor and we have generated molecules more potent and selective than the reference 7-OH-DPAT. In in vivo experiment with 6- OHDA-induced unilaterally lesioned rats, one of our lead analogs produced potent contralateral rotations with a long duration of action. We now propose to expand on our initial findings through comprehensive SAR studies with various pharmacological characterizations to develop potent D3-preferring compounds. Furthermore, in our effort to understand molecular interaction of our novel hybrid molecules with the D3 receptor, we will carry out site-directed mutagenesis studies with the selected D3 mutants and will perform molecular modeling studies using a comprehensive training set of agonist molecules. Results from these experiments will help us to build a pharmacophore model for interaction of novel hybrid molecules with the D2/D3 receptors. Finally, we will test whether the two most active compounds developed in the above experiments can provide neuroprotection to dopaminergic neurons in vivo experiments with mice treated with MPTP and whether such an effect is mediated by the DS-receptor.